Capsaicinoid gel formulation and uses thereof

Abstract

The present invention provides capsaicinoid gel formulations and methods for relieving pre- and post-surgical pain at a site in a human or animal by administering at a surgical site in a human or animal in need thereof a dose of capsaicinoid gel in an amount effective to attenuate post-surgical pain at the surgical site, the dose of capsaicin ranging from 100 μg to 10,000 μg.

1 . A method for treating post-surgical pain at a site in a human or animal comprising: 
 administering intra-operatively at a surgical site in a human or animal in need thereof a single dose of capsaicinoid gel in an amount effective to attenuate or relieve post-surgical pain at the surgical site without eliciting an effect outside the surgical site and to attenuate or relieve pain emanating from the surgical site, the dose ranging from about 100 μg to about 10,000 μg capsaicin or a therapeutically equivalent dose of a capsaicinoid other than capsaicin.    
   
   
       2 . The method of  claim 1 , wherein said dose of capsaicin is from about 500 to about 5000 μg.  
   
   
       3 . The method of  claim 1 , wherein said dose of capsaicin is from about 1000 to about 3000 μg.  
   
   
       4 . The method of  claim 1 , wherein said dose of capsaicinoid is administered in a pharmaceutically and physiologically acceptable base for topical administration.  
   
   
       5 . The method of  claim 4 , wherein said pharmaceutically acceptable base is a surfactant selected from the group consisting of a polysorbate and any combinations or mixtures thereof.  
   
   
       6 . The method of  claim 5 , wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and any combinations or mixtures thereof.  
   
   
       7 . The method of  claim 6 , wherein said base is polysorbate 80.  
   
   
       8 . The method of  claim 5 , wherein said dose of capsaicinoid is further administered in a pharmaceutically and physiologically acceptable gelling agent selected from the group consisting of carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, guar gum, karaya gum, xanthan gum, locust bean gum, alginic acid, starch, tragacanth, carboxyvinyl polymers and any combinations or mixtures thereof.  
   
   
       9 . The method of  claim 8 , wherein said gelling agent is hydroxypropylmethylcellulose.  
   
   
       10 . The method of  claim 9 , wherein said capsaicinoid is further administered in a pharmaceutically and physiologically acceptable excipient selected from the group consisting of a tonicity agent, a viscosity increasing agent, a co-surfactant, a buffering agent and any combinations or mixtures thereof.  
   
   
       11 . The method of  claim 10 , wherein said tonicity agent is a pharmaceutically acceptable sugar or salt that is present in an amount from about 100 mOsm/kg to about 500 mOsm/kg.  
   
   
       12 . The method of  claim 10 , wherein said tonicity agent is a pharmaceutically acceptable sugar or salt that is present in an amount from about 280 mOsm/kg to about 320 mOsm/kg.  
   
   
       13 . The method of  claim 10 , wherein said tonicity agent is selected from the group consisting of dextrose, sodium chloride and any combinations or mixtures thereof.  
   
   
       14 . The method of  claim 10 , wherein said viscosity increasing agent is selected from the group consisting of bentonite, carbomer, ceratonia, cetostearyl alcohol, chitosan, colloidal silicon dioxide, cyclomethicone, hypromellose, magnesium aluminum silicate, maltitol, maltodextrin, medium chain triglycerides, polydextrose, polyvinyl alcohol, propylene glyceryl alginate, sodium alginate, tragacanth and any combinations or mixtures thereof.  
   
   
       15 . The method of  claim 1 , wherein said dose of capsaicinoid gel is administered intra-operatively to the cut surface of skin, tissue, muscle and bone at the surgical site.  
   
   
       16 . The method of  claim 1 , further comprising co-administering a local anesthetic with said dose of capsaicinoid gel in an amount and location effective to attenuate an initial hyperalgesic effect of said administered dose of capsaicinoid.  
   
   
       17 . The method of  claim 16 , wherein said local anesthetic is selected from the group consisting of dibucaine, bupivacaine, ropivacaine, etidocaine, tetracaine, procaine, chlorocaine, prilocalne, mepivacaine, lidocaine, xylocalne, 2-chloroprocaine, and acid addition salts or mixtures thereof.  
   
   
       18 . The method of  claim 16 , wherein said local anesthetic is administered by direct injection into the site where said dose of capsaicinoid gel is administered.  
   
   
       19 . The method of  claim 16 , wherein said local anesthetic is administered topically to the site where said dose of capsaicinoid gel is administered.  
   
   
       20 . The method of  claim 16 , wherein said local anesthetic is administered to said site as a regional nerve block.  
   
   
       21 . The method of  claim 1 , further comprising co-administering phenol with said dose of capsaicinoid gel in an amount and location effective to attenuate an initial hyperalgesic effect of said administered dose of capsaicinoid gel.  
   
   
       22 . The method of  claim 1 , wherein said administration of capsaicinoid gel at said surgical site provides relief from post-surgical pain emanating from said site for at least about 48 hours up to about 16 weeks.  
   
   
       23 . The method of  claim 1 , wherein said capsaicinoid comprises capsaicin.  
   
   
       24 . The method of  claim 1 , wherein said capsaicinoid is other than capsaicin.  
   
   
       25 . The method of  claim 21 , wherein said capsaicinoid is selected from the group consisting of resiniferatoxin, N-vanillylnonanamides, N-vanillylsulfonamides, N-vanillylureas, N-vanillylcarbamates, N[(substituted phenyl)methyl]alkylamides, methylene substituted N[(substituted phenyl)methyl]alkanamides, N[(substituted phenyl) methyl]-cis-monosaturated alkenamides, N[(substituted phenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide, hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin, nordihydrocapsaicin anandamide, piperine, zingerone, warburganal, polygodial, aframodial, cinnamodial, cinnamosmolide, cinnamolide, isovelleral, scalaradial, ancistrodial, α-acaridial, merulidial, scutigeral, and any combinations or mixtures thereof.  
   
   
       26 . The method of  claim 25 , wherein said capsaicinoid is resiniferatoxin.  
   
   
       27 . The method of  claim 23 , wherein said capsaicin consists essentially of ultra-purified trans-capsaicin.  
   
   
       28 . The method of  claim 27 , wherein said capsaicin consist essentially of 97% trans-capsaicin.  
   
   
       29 . The method of  claim 27 , wherein said capsaicin consist essentially of 98% trans-capsaicin.  
   
   
       30 . The method of  claim 27 , wherein said capsaicin consist essentially of 99% trans-capsaicin.  
   
   
       31 . The method of  claim 27 , wherein said capsaicin is natural or synthetic capsaicin.  
   
   
       32 . The method of  claim 1 , wherein said post-surgical pain is associated with median sternotomy, and the method further comprises administering to sternal edges of a human or animal undergoing a median sternotomy a single dose of capsaicinoid gel in an amount effective to denervate said sternal edges without eliciting an effect outside the sternal edge location, said dose of capsaicin gel ranging from about 11 g to about 3000 μg.  
   
   
       33 . The method of  claim 1 , wherein said post-surgical pain is associated with chronic post-herniorrhapy, and the method further comprises administering to a site where hernia surgery was performed in a human or animal a single dose of a capsaicin gel in an amount effective to denervate said site, said dose of capsaicin gel ranging from about 500 μg to about 5000 μg.  
   
   
       34 . The method of  claim 1 , wherein said post-surgical pain is associated with laparoscopic cholecystectomy, and the method further comprises administering to a site where said laparoscopic cholecystectomy was performed in a human or animal a single dose of a capsaicin gel in an amount effective to denervate said site, said dose of capsaicin gel ranging from about 500 μg to about 5000 μg.  
   
   
       35 . The method of  claim 1 , wherein said post-surgical pain is associated with a bunionectomy, and the method further comprises administering into a wound opening resulting from a bunionectomy surgical procedure in a human or animal a single dose of a capsaicin gel in an amount effective to denervate said wound opening, said dose of capsaicin gel ranging from about 500 μg to about 5000 μg.  
   
   
       36 . The method of  claim 1 , wherein said post-surgical pain is associated with a knee replacement, and, the method further comprises administering into a wound opening resulting from a knee replacement surgical procedure in a human or animal a single dose of a capsaicin gel in an amount effective to denervate said wound opening, said dose of capsaicin gel ranging from about 500 μg to about 5000 μg.  
   
   
       37 . The method of  claim 1 , wherein said post-surgical pain is associated with a mastectomy, and the method further comprises administering into a wound opening resulting from a mastectomy surgical procedure in a human or animal a single dose of a capsaicin gel in an amount effective to denervate said wound opening, said dose of capsaicin gel ranging from about 500 μg to about 5000 μg.  
   
   
       38 . The method of  claim 1 , wherein said dose of capsaicinoid is therapeutically equivalent to a dose of capsaicin in an amount from about 100 to about 10,000 μg.  
   
   
       39 . The method of  claim 1 , wherein said dose of capsaicinoid is therapeutically equivalent to a dose of capsaicin in an amount from about 500 to about 5000 μg.  
   
   
       40 . The method of  claim 1 , wherein said capsaicinoid comprises a mixture of capsaicinoids in a total amount equivalent to a capsaicin dose from about 100 μg to about 10,000 μg of capsaicin.  
   
   
       41 . The method of  claim 1 , further comprising administering to said patient an analgesic to treat breakthrough pain.  
   
   
       42 . The method of  claim 1 , further comprising co-administering with said capsaicinoid an additional biologically active agent selected from the group consisting of an anti-bacterial agent, antiviral agent, antifungal agent, antiparasitic agent, steroidal antiinflammatory agent, antihistamine, anesthetic, analgesic, antineoplastic and any combinations or mixtures thereof.  
   
   
       43 . A topical gel formulation for attenuating or relieving post-surgical pain at a surgical site in a human or animal in need thereof, comprising a capsaicinoid selected from the group consisting of from 100 μg to 10,000 μg of capsaicin, a therapeutically equivalent amount of one or more other capsaicinoids, and combinations thereof, a pharmaceutically and physiologically acceptable base and a pharmaceutically and physiologically acceptable gelling agent.  
   
   
       44 . The pharmaceutical formulation of  claim 43 , wherein said capsaicinoid comprises from about 500 μg to 5000 μg capsaicin.  
   
   
       45 . The pharmaceutical formulation of  claim 43 , wherein said capsaicinoid comprises from about 1000 μg to 3000 μg capsaicin.  
   
   
       46 . The pharmaceutical formulation of  claim 45 , wherein said capsaicin is at least about 97% trans-capsaicin.  
   
   
       47 . The pharmaceutical formulation of  claim 45 , wherein said trans-capsaicin is at least about 98% trans-capsaicin.  
   
   
       48 . The pharmaceutical formulation of  claim 45 , wherein said trans-capsaicin is at least about 99% trans-capsaicin.  
   
   
       49 . The pharmaceutical formulation of  claim 43 , wherein said pharmaceutically acceptable base is a surfactant selected from the group consisting of a polysorbate and any combinations or mixtures thereof.  
   
   
       50 . The pharmaceutical formulation of  claim 49 , wherein said polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and any combinations or mixtures thereof.  
   
   
       51 . The pharmaceutical formulation of  claim 50 , wherein said base is polysorbate 80.  
   
   
       52 . The pharmaceutical formulation of  claim 43 , wherein said pharmaceutically and physiologically acceptable gelling agent is selected from the group consisting of carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, guar gum, karaya gum, xanthan gum, locust bean gum, alginic acid, starch, tragacanth, carboxyvinyl polymers and any combinations or mixtures thereof.  
   
   
       53 . The pharmaceutical formulation of  claim 52 , wherein said gelling agent is hydroxypropylmethylcellulose.  
   
   
       54 . The pharmaceutical formulation of  claim 43 , further comprising a pharmaceutically and physiologically acceptable excipient selected from the group consisting of a tonicity agent, a viscosity increasing agent, a surfactant, a buffering agent and any combinations or mixtures thereof.  
   
   
       55 . The pharmaceutical formulation of  claim 54 , wherein said tonicity agent is a pharmaceutically acceptable sugar or salt that is present in an amount from about 100 mOsm/kg to about 500 mOsm/kg.  
   
   
       56 . The pharmaceutical formulation of  claim 54 , wherein said tonicity agent is a pharmaceutically acceptable sugar or salt that is present in an amount from about 280 mOsm/kg to about 320 mOsm/kg.  
   
   
       57 . The pharmaceutical formulation of  claim 54 , wherein said tonicity agent is selected from the group consisting of dextrose, sodium chloride and any combinations or mixtures thereof.  
   
   
       58 . The pharmaceutical formulation of  claim 54 , wherein said viscosity increasing agents are selected from the groups consisting of bentonite, carbomer, ceratonia, cetostearyl alcohol, chitosan, colloidal silicon dioxide, cyclomethicone, hypromellose, magnesium aluminum silicate, maltitol, maltodextrin, medium chain triglycerides, polydextrose, polyvinyl alcohol, propylene glyceryl alginate, sodium alginate, tragacanth and any combinations or mixtures thereof.  
   
   
       59 . The pharmaceutical formulation of  claim 43 , further comprising water for injection, wherein the concentration of gelling agent in said water being sufficient to provide said gel formulation with a final viscosity from about 100 cP to 50,000 cP.  
   
   
       60 . The formulation of  claim 59 , wherein said viscosity is in the range from about 300 cP to about 320 cP.  
   
   
       61 . The formulation of  claim 59 , wherein said viscosity is greater than 50,000 cP.  
   
   
       62 . The formulation of  claim 55 , further comprising an additional biologically active agent selected from the group consisting of an anti-bacterial agent, antiviral agent, antifungal agent, antiparasitic agent, steroidal antiinflammatory agent, antihistamine, anesthetic, analgesic, antineoplastic and any combinations or mixtures thereof.  
   
   
       63 . The gel formulation of  claim 55 , wherein said gel formulation further comprises a preservative selected from the group consisting of benzoic acid, boric acid, p-hydroxybenzoates, phenols, chlorinated phenolic compounds, alcohols, quarternary compounds, mercurials, and any mixtures of the foregoing.